Abstract 20

Congenital Factor XIII (FXIII) deficiency is a rare autosomal recessive disorder affecting approximately 1 in 2–5 million individuals without gender or ethnic predilection. The plasma form of FXIII is a heterotetramer [A2B2] comprising two FXIII-A subunits and two FXIII-B subunits. A-subunit deficiency predominates (95%). FXIII deficient patients have a high risk of life-threatening bleeds, notably spontaneous intracranial haemorrhage. They experience impaired wound healing, and recurrent first trimester spontaneous abortions. Given the severity of the disorder there is a clinical need for providing effective haemostatic replacement therapy. Currently, only plasma derived products are approved for use in the United States. These may carry a risk of blood borne infection, sensitization and allergic reactions.

A multi-center, multi-national, open-label, single-arm, multiple dosing phase 3 (prophylaxis) trial was undertaken to evaluate the efficacy and safety of a novel recombinant FXIII (rFXIII) in the prevention of bleeds in congenital FXIII-A subunit deficiency. This rFXIII-A2 dimer is expressed in Saccharomyces Cerevisiae and is an exact copy of the human A-subunit, which is the active cross-linking enzyme. When rFXIII is administered, it immediately binds to the B subunit that is present in the bloodstream. Forty-one patients aged ≥7 years [mean: 26.4 (range: 7–60); 23 males; 18 females] with a diagnosis of severe congenital FXIII-A subunit deficiency were enrolled. Patients entered a 4-week run-in period followed by monthly treatment with 35 IU/kg of rFXIII for 52 weeks. Informed consent was obtained prior to any trial-related activities. Bleeding episodes and adverse events were recorded. Testing was conducted monthly to measure pre- and post-dose FXIII activity and concentration, 5M urea clot solubility and anti-FXIII antibodies. Where antibodies were found, detailed testing for neutralizing potential was performed. Data were compared with bleeding rates based on historical data.

During the treatment period with rFXIII (466 patient months) five bleeding episodes treated with FXIII-containing products were observed in four patients. All five were associated with trauma. No spontaneous bleeds that require treatment or intracranial haemorrhage occurred during rFXIII treatment period in any of the patients. The annual rate of bleeds requiring treatment was estimated via a Poisson model to be 0.048 bleeds/patient/year (95% CI: [0.0094; 0.2501] - significantly lower than the historic bleeding rate of 2.91 (p<0.0001). The crude mean rate of bleeding was 0.138 bleeds/patient/year. The occurrence of bleeds requiring treatment was not associated with low FXIII activity levels in study patients. The average FXIII activity at 1 hr post-dose was 77.0 ± 20.3% (mean±SD). The mean incremental increase in activity from pre-dose to 1 hr post-dose was 1.68 ± 0.51% /IU/ kg. Four patients developed transient, non-neutralizing, low-titer anti-rFXIII antibodies. None of these patients developed anaphylactic or allergic reactions, bleeding episodes or changes in FXIII pharmacokinetics at any time. Furthermore, the non-neutralizing antibodies declined below the limit of detection in all patients despite repeated exposure to rFXIII or other FXIII containing products. Consequently, these low titer, non-neutralizing antibodies appear to be clinically insignificant. No clinical safety issues, thromboembolic events, or fatal adverse events were recorded. In conclusion, rFXIII-A2 is safe and effective prophylaxis for preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency.


Inbal:NovoNordisk: Honoraria, Research Funding. Oldenburg:novonordisk: Research Funding. Carcao:NovoNordisk: Research Funding. Rosholm:NovoNordisk: Employment. Tehranchi:NovoNordisk: Employment. Nugent:NovoNordisk: Consultancy, Research Funding.

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Author notes


Asterisk with author names denotes non-ASH members.